Published OnlineFirst December 3, 2012; DOI: 10.1158/1078-0432.CCR-12-3002
Clinical
Cancer
Research
Review
The Definition of Primary and Secondary Glioblastoma
Hiroko Ohgaki1 and Paul Kleihues2
Abstract
Glioblastoma is the most frequent and malignant brain tumor. The vast majority of glioblastomas
(90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less
malignant precursor lesion (primary glioblastomas). Secondary glioblastomas progress from low-grade
diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of
necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary glioblastomas are largely indistinguishable, but they differ in their genetic and
epigenetic profiles. Decisive genetic signposts of secondary glioblastoma are IDH1 mutations, which are
absent in primary glioblastomas and which are associated with a hypermethylation phenotype. IDH1
mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in
oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from
those of primary glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic,
genetic, and expression features of primary and secondary glioblastomas and the biologic consequences of
IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of
secondary glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic
appearance, primary and secondary glioblastomas are distinct tumor entities that originate from different
precursor cells and may require different therapeutic approaches. Clin Cancer Res; 19(4); 764–72. 2012
AACR.
Introduction
Historical perspective
From a biologic and clinical point of view, the secondary
glioblastomas developing in astrocytomas must be distinguished
from "primary" glioblastomas. They are probably responsible for
most of the glioblastomas of long clinical duration.
H.-J. Scherer (1940; ref. 1).
In a series of publications on gliomas, Hans-Joachim
Scherer (1906–1945), a young German neuropathologist
working in exile at the Institut Bunge (Antwerp, Belgium)
was decades ahead of his contemporaries in his insight
into the pathology and biology of brain tumors (2). The
distinction between primary and secondary glioblastomas
was a remarkable observation at that time. In the first
edition of the World Health Organization (WHO) Classification of Tumors of the Nervous System, published 40
years later, glioblastomas were not even recognized as
astrocytic neoplasms but listed in a group of "poorly
Authors' Affiliations: 1Molecular Pathology Section, International Agency
for Research on Cancer, Lyon, France; and 2Department of Pathology,
University Hospital Zurich, Zurich, Switzerland
Corresponding Author: Hiroko Ohgaki, Molecular Pathology Section,
International Agency for Research on Cancer, 150 Cours Albert Thomas,
69372 Lyon, France. Phone: 33-4-72-73-85-34; Fax: 33-4-72-73-86-98;
E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-12-3002
2012 American Association for Cancer Research.
764
differentiated and embryonal tumors" (3). Only after the
introduction of immunohistochemistry was their astrocytic origin unequivocally established (4). Although it was
recognized in clinical practice that some glioblastomas
developed after resection of low-grade or anaplastic astrocytomas, Scherer’s distinction remained conceptual as
histopathologically these subtypes could not reliably be
distinguished.
In 1996, we reported evidence that primary and secondary glioblastomas carry distinct genetic alterations (5). TP53
mutations were found to be uncommon in primary glioblastomas but occurred with a high incidence in secondary
glioblastomas; EGF receptor (EGFR) overexpression prevailed in primary glioblastomas but was rare in secondary
glioblastomas. Only 1 of 49 glioblastomas showed TP53
mutation and EGFR overexpression, indicating that these
alterations are mutually exclusive events defining 2 different
genetic pathways in the evolution of glioblastoma (5).
Subsequently, many studies provided evidence that primary
and secondary glioblastomas develop through distinct
genetic pathways (6, 7). Typical for primary glioblastomas
are EGFR amplification, PTEN mutation, and entire loss of
chromosome 10 (6–8). Genetic alterations more common
in secondary glioblastomas include TP53 mutations and
19q loss (6, 7, 9). However, until the identification of IDH1
mutation as a molecular marker of secondary glioblastoma
(10–13), the patterns of genetic alterations, though different, did not allow an unequivocal separation of the 2
subtypes.
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Definition of Primary and Secondary Glioblastomas
IDH1 Mutations as Initiator and Lineage Marker in
Gliomagenesis
IDH1/2 mutations in neural tumors
IDH1 mutations were first reported by Parsons and colleagues (14) in 2008, and in this first study the authors
already pointed out that "mutations in IDH1 occurred in a
large fraction of young patients and in most patients with
secondary glioblastomas and were associated with an
increase in overall survival." Subsequent studies showed that
these mutations are very frequent in secondary (>80%) but
very rare in primary glioblastomas (<5%; refs. 10–13). IDH1
mutations as a genetic marker of secondary, but not primary,
glioblastoma closely correspond to the respective clinical
diagnosis in 385 of 407 (95%) of cases (13). It is now agreed
that IDH1 mutation is a definitive diagnostic molecular
marker of secondary glioblastomas and more reliable and
objective than clinical and/or pathologic criteria.
IDH1 mutations are frequent (>80%) in diffuse astrocytoma WHO grade II and anaplastic astrocytoma WHO grade
III, the precursor lesions of secondary glioblastomas, as well
as in oligodendroglial tumors including oligodendroglioma WHO grade II, anaplastic oligodendroglioma WHO
grade III, oligoastrocytoma WHO grade II, and anaplastic
oligoastrocytoma WHO grade III (10–12, 15). In contrast,
IDH1 mutations are very rare or absent in pilocytic astrocytomas, as well as in most other CNS neoplasms, including
ependymomas, medulloblastomas, and meningiomas (10–
12, 15). IDH2 mutations are less frequent and prevail in
anaplastic oligodendrogliomas (5%) and oligoastrocytomas (6%; ref. 12).
All IDH1 mutations reported are located at the first or
second base of codon 132 (10, 11, 14). Most frequent is
R132H (CGT-->CAT), observed in 83% to 91% of IDH1
mutations in astrocytic and oligodendroglial gliomas
(10–12). Other mutations are rare, including R132C
(CGT-->TGT; 3.6%–4.6%; refs. 10–12), R132G (0.6%–
3.8%; refs. 10–12), R132S (0.8%–2.5%; refs. 10–12), and
R132L (0.5%–4.4%; refs. 10, 12). IDH2 mutations are
located at codon 172 (12), with R172K being most frequent.
IDH1/2 mutations in non-neural tumors
IDH1/2 mutations are absent or very rare in most tumors
at other organ sites, including bladder, breast, stomach,
colorectum, lung, liver, ovary, and prostate (12, 15). Exceptions are central chondrosarcomas (55%; ref. 16),
intrahepatic cholangiocarcinomas (23%; ref. 17), acute myelogenous leukemia (AML; 15%–20%; refs. 18–23), angioimmunoblastic T-cell lymphoma (AITL; 20%; ref. 24), malignant melanoma (10%; ref. 25), and anaplastic thyroid
cancer (10%; ref. 26). This suggests that IDH1/2 mutations
may confer a growth advantage in specific cell lineages at
defined stages of development and differentiation.
Are there primary glioblastomas with IDH1 mutations?
In a population-based study, only 14 of 407 glioblastomas clinically diagnosed as primary (3.4%) carried an IDH1
mutation (13). These patients were 10 years younger and
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their genetic profiles were similar to those of secondary
glioblastomas, including frequent TP53 mutations and
absence of EGFR amplification (13). Similarly, several hospital-based studies showed that primary glioblastomas with
IDH1 mutations were 13 to 27 years younger than those
without IDH1 mutations (10, 12, 27, 28). Toedt and colleagues (27) showed that primary glioblastomas with IDH1
mutations have gene expression profiles similar to those of
IDH1-mutated secondary glioblastomas. Glioblastomas
with IDH1 mutations clinically diagnosed as primary may
have rapidly progressed from precursor lesions that escaped
clinical diagnosis and are likely to have been misclassified as
primary glioblastoma.
Are there secondary glioblastomas that do not have
IDH1 mutations?
Secondary glioblastomas lacking IDH1 mutations have
infrequent TP53 mutations and patients have a shorter
clinical history (13). Furthermore, most secondary glioblastomas lacking IDH1 mutations (7 of 8) had developed
through progression from an anaplastic glioma (WHO
grade III), whereas the majority of secondary glioblastomas
with IDH1 mutations had progressed from a WHO grade II
glioma (13). The possibility therefore exists that some
tumors diagnosed as anaplastic astrocytoma were actually
primary glioblastomas that were misdiagnosed because of a
sampling error. In the absence of diagnostic hallmarks, that
is, necrosis and/or microvascular proliferation, pathologists
hesitate to make a diagnosis of glioblastoma even if MRI
suggests this.
Timing of IDH1/2 mutations in the pathway to
secondary glioblastoma
IDH1/2 mutations are an early event in gliomagenesis
and persist during progression to secondary glioblastoma.
In addition to frequent IDH1/2 mutations, about 65% of
diffuse astrocytomas carry a TP53 mutation, whereas oligodendrogliomas show frequent 1p/19q loss (>75%;
refs. 11, 29–33). IDH1/2 mutations are likely to occur
before TP53 mutation or 1p/19q loss, as low-grade diffuse
gliomas carrying only IDH1/2 mutations are more frequent
(17%) than those carrying only a TP53 mutation (2%) or
those showing only 1p/19q loss (3%; ref. 33). Furthermore,
the analysis of multiple biopsies from the same patient
revealed that there were no cases in which an IDH1 mutation occurred after the acquisition of a TP53 mutation or
loss of 1p/19q (11, 33).
Acquisition of 1p/19q loss in cells with IDH1/2 mutations may be the driving force toward oligodendroglial
differentiation in low-grade diffuse glioma (11, 31, 33). It
has been shown that tumors with the typical histologic
signature of oligodendroglioma (e.g., honeycomb appearance of most neoplastic cells) showed loss at 1p/19q in the
vast majority of cases (>90%; ref. 31). Furthermore, exomic
sequencing recently revealed that mutations in the CIC gene
(homolog of the Drosophila gene capicua) at 19q13.2 and in
the FUBP1 gene at 1p are frequent in oligodendrogliomas
but rare or absent in diffuse astrocytomas (34–36).
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Ohgaki and Kleihues
Astrocytomas typically develop in cells with IDH1/2
mutations that subsequently acquire TP53 mutations.
Recent studies have also described mutations in the ATRX
(a-thalassemia/mental-retardation-syndrome-X-linked)
gene that are often copresent with IDH1/2 mutations and
TP53 mutations in diffuse astrocytomas WHO grades II/III
and secondary glioblastomas (36, 37). Our current concept
of the genetic pathways leading to astrocytic and oligodendroglial gliomas is summarized in Figure 1.
Only 7% of WHO grade II diffuse gliomas had none of
these genetic alterations (i.e., IDH1/2 mutations, TP53
mutations, and 1p/19q loss) and were termed "triple negative" (33). These cases are still poorly understood; a minor
fraction shows loss of cell-cycle control regulated by the RB1
pathway (38). The possibility cannot be excluded that they
are derived from a different precursor cell population.
IDH1 mutations in gliomas associated with the
Li-Fraumeni syndrome
As indicated earlier, IDH1 mutations precede TP53 mutations in sporadic astrocytic tumors. Patients with Li-Fraumeni syndrome (LFS) carry a germline TP53 mutation that
is present in every somatic cell. Thus, by definition TP53
mutations would be the first event in LFS-associated gliomas, which account for 12% to 13% of all tumors occurring
in LFS families (39, 40). In patients from 3 families with LFS,
we identified IDH1 mutations in 5 astrocytic gliomas that
developed in carriers of a TP53 germline mutation. Without
exception, all contained the R132C (CGT-->TGT) mutation
(41), which in sporadic astrocytic tumors amounts to less
Glial progenitor cells
than 5% of all IDH1 mutations (10–12). This remarkably
selective occurrence suggests a preference for R132C mutations in neural precursor cells that already carry a germline
TP53 mutation.
Biologic Consequences of IDH Mutations
The mechanisms by which IDH1 mutations contribute to
the development and malignant progression of astrocytic
and oligodendroglial tumors are still not fully understood.
Conditional IDH1 (R132H) knockin mice with expression
in all hematopoietic cells or cells of the myeloid lineage
caused an increased number of early hematopoietic progenitors with splenomegaly, anemia, and extramedullary
hematopoiesis (42), whereas brain-specific IDH1 (R132H)conditional knockin mice exhibited hemorrhage and perinatal lethality (43). Like EGFR amplification in primary
glioblastomas, IDH1 mutations in secondary glioblastomas
are typically lost during culture in vitro (44). This is enigmatic, since selective suppression of endogenous mutant
IDH1 expression in a fibrosarcoma cell line with a native
IDH1R132C heterozygous mutation significantly inhibits
cell proliferation (45). Only recently, using a neurosphere
culture method, it has been possible to establish a brain
tumor stem cell line from an IDH1-mutant anaplastic
oligoastrocytoma with an endogenous IDH1 mutation and
detectable production of 2-hydroxyglutarate (2HG; ref. 46).
This may suggest that IDH1-mutant glioma cells have stem
cell–like features that confer a growth advantage under
neurosphere culture conditions. Alternatively, there may
be intratumoral heterogeneity of IDH1 mutations, and
Glial progenitor cells
Common precursor cells with IDH1/2 mutation
3–6 mo
clinical history
TP53 mutation (~65%)
ATRX mutation (~65%)
Loss 1p/19q (>75%)
CIC mutation (~40%)
FUBP1 mutation (~15%)
Diffuse astrocytoma
Oligodendroglioma
WHO
grade
II
~5 y
EGFR amplification (~35%)
TP53 mutation (~30%)
PTEN mutation (~25%)
LOH 10p (~50%)
LOH 10q (~70%)
Primary
glioblastoma
Neural, classical, mesenchymal,
proneural transcriptional profiles
Anaplastic
astrocytoma
LOH 19q (~50%)
LOH 10q (>60%)
Anaplastic
oligodendroglioma
III
Figure 1. Genetic pathways to
primary and secondary
glioblastomas. Note that only
secondary glioblastomas share
common origin of cells with
oligodendrogliomas.
~2 y
Secondary
glioblastoma
IV
Proneural transcriptional profile
Hypermethylation phenotype
© 2012 American Association for Cancer Research
766
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Definition of Primary and Secondary Glioblastomas
neoplastic cells lacking IDH1 mutations are positively
selected during culture.
observed in IDH1-mutant and glioma–CpG island methylator phenotype (G-CIMP)þ primary gliomas (59).
Impaired enzymatic activity and accumulation of
2-hydroxyglutarate
The IDH1 gene encodes isocitrate dehydrogenase 1, an
enzyme participating in the citric acid (Krebs) cycle (47, 48),
the metabolic pathway used by aerobic organisms to generate usable energy (49). IDH1/2 mutations reduce the wildtype activity of the enzyme, that is, the conversion of
isocitrate to a-ketoglutarate (a-KG), and increase levels of
hypoxia-inducible factor-1a (HIF-1a), a transcription factor, and its targets (e.g., GLUT1, VEGF, and PGK1; ref. 50).
Importantly, IDH1/2 mutations are gain-of-function mutations that also produce the oncometabolite 2HG from a-KG
(51, 52). The production of 2HG is a function shared by all
the commonly occurring IDH1/2 mutants analyzed (51–
53). Malignant IDH1mut gliomas contain an increased (up
to 100-fold) concentration of 2HG (51). Cells from brainspecific IDH1 (R132H)-conditional knockin mice also
show high levels of 2HG that are associated with inhibited
prolyl-hydroxylation of HIF-1a and upregulation of its
target genes (43). 2HG also blocks prolyl-hydroxylation of
collagen, causing a defect in collagen protein maturation,
leading to basement-membrane aberrations that may play a
role in glioma progression (43).
IDH1 Mutations and the Proneural Signature of
Glioblastomas
Hypermethylation phenotype
Noushmehr and colleagues (54) first reported that IDH1/
2mut glioblastomas displayed concerted CpG island methylation at a large number of loci. A similar hypermethylation
phenotype was also observed in IDH1/2mut diffuse astrocytomas (55) and oligodendroglial tumors (55), as well as in
IDH1/2mut AML (56). Turcan and colleagues (57) introduced
mutant IDH1 into primary human astrocytes, causing alteration of specific histone markers and induction of extensive
DNA hypermethylation, suggesting that the presence of an
IDH1 mutation is sufficient to establish a hypermethylation
phenotype in glioma. This is supported by the observation
that the expression of IDH1 (R132H) in cells of myeloid
lineage in knockin mice resulted in hypermethylated histones and changes in DNA methylation similar to those
observed in human IDH1/2mut AML (42). Stable transfection
of a 2HG-producing IDH mutant into immortalized astrocytes resulted in progressive accumulation of histone methylation, which was associated with repression of the inducible expression of lineage-specific differentiation genes and a
block to differentiation, suggesting that 2HG-producing
IDH1/2 mutants can prevent the histone demethylation that
is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells (58). Duncan and
colleagues (59) knocked in a single copy of the IDH1 R132H
into a human cancer cell line and profiled changes in DNA
methylation in more than 27,000 CpG dinucleotides. Heterozygous expression of mutant IDH1 was sufficient to
induce widespread alterations in DNA methylation, including hypermethylation of 2,010 and hypomethylation of
842 CpG loci, many of which were consistent with those
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Glioblastomas have been classified on the basis of cDNA
expression profiles, with distinct proneural, neural, classical,
mesenchymal, and proliferative patterns (60, 61). Most
IDH1mut glioblastomas (11 of 12, 92%) show a proneural
expression signature; conversely, approximately 30% of glioblastomas with a proneural signature are IDH1mut (61).
Glioblastomas lacking IDH1 mutations have all been identified as classical, mesenchymal, neural, or proneural (61).
These observations suggest that secondary glioblastomas
are a rather homogeneous group of tumors characterized by
a proneural expression pattern, whereas primary glioblastomas are heterogeneous, with several distinct expression
profiles. Diffuse astrocytomas, oligodendrogliomas, and
oligoastrocytomas all show the typical proneural signatures
(62), again supporting the view that these neoplasms share
common neural progenitor cells.
Incidence of Secondary Glioblastomas
Until the discovery of IDH1 mutations as a molecular
marker, the distinction between primary and secondary
glioblastomas was based on clinical observations. Tumors
were considered primary if the diagnosis of glioblastoma
was made at the first biopsy, without radiologic or histologic evidence of a preexisting, less malignant precursor
lesion. The diagnosis of secondary glioblastoma required
neuroimaging and/or histologic evidence of a preceding
low-grade or anaplastic astrocytoma (6, 7).
In developed countries, the annual incidence of glioblastomas is usually in the range of 3 to 4 cases per 100,000
persons per year (7, 63–65). In a population-based study in
Switzerland, using clinical criteria and histopathologic evidence, only 5% of all glioblastomas diagnosed were secondary (7, 63). Similarly, a study by the University of
Alabama (Tuscaloosa, AL) showed that 19 of 392 (5%)
cases of glioblastoma had a histologically proven prior lowgrade glioma (66). When IDH1 mutations are used as a
genetic marker, secondary glioblastomas accounted for 9%
of all glioblastomas at the population level (13) and for 6%
to 13% in hospital-based studies (10, 12, 67, 68).
The combined incidence rates of low-grade and anaplastic astrocytomas are approximately twice as high as that of
clinically diagnosed secondary glioblastoma or IDH1mut
glioblastoma (30, 64, 69). This may be explained at least
in part by the fact that some patients with low-grade or
anaplastic astrocytoma succumb to the disease before progression to glioblastoma occurs. Furthermore, cases with
rapid progression from low-grade or anaplastic astrocytoma
may be misclassified as primary glioblastoma.
Age and Sex Distribution
There is a striking difference in the age distribution of
patients with primary and secondary glioblastoma. At a
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Ohgaki and Kleihues
population level, the mean age of patients with glioblastoma clinically diagnosed as primary was 62 years, whereas
secondary glioblastomas developed in younger patients
(mean, 45 years; refs. 7, 63). Similarly, the mean ages of
patients with or without IDH1 mutations were 61 and 48
years, respectively (Table 1; ref. 13). Several hospital-based
studies showed that patients with IDH1mut glioblastoma
are significantly younger (mean age, 32–41 years) than
those without IDH1 mutations (mean age, 56–59 years;
refs. 12, 67, 70).
Glioblastomas predominantly affect males, with a population-based M/F ratio ranging from 1.28 (7) to 1.32 (64,
65). In contrast, diffuse astrocytomas (WHO grade II) have
a less pronounced male predominance, with M/F ratios of
approximately 1.17 (29, 65). Because secondary glioblastomas typically develop from diffuse astrocytomas, one
would expect that they have a similar gender ratio. This is
indeed the case. In a population-based study, IDH1mut
secondary glioblastomas had an M/F ratio of 1.12, significantly lower than the ratio of 1.46 in patients with primary
glioblastoma (7). Several hospital-based studies also
showed a tendency toward a lower M/F ratio of patients
with secondary glioblastomas (5, 71–74). In a recent multicenter study, 49 of 618 glioblastomas (7.9%) carried an
IDH1 mutation and had an M/F ratio of 0.96, in contrast to a
ratio of 1.63 for nonmutated (primary) glioblastomas (68).
Clinical History
At a population level, the majority of patients with
primary glioblastoma (68%) had a clinical history of less
than 3 months (6). The mean duration of the clinical history
of patients with primary and secondary glioblastoma was
6.3 and 16.8 months, respectively (7, 63). Similarly,
patients with glioblastomas lacking IDH1 mutations had
a mean duration of preceding clinical symptoms of 3.9
months, significantly shorter than patients with IDH1mut
glioblastoma (mean, 15.2 months; P ¼ 0.0003; ref. 13).
Glioblastomas clinically diagnosed as primary had a mean
clinical history of about 4 (IDHwt) and 29 months (IDHmut),
respectively (13). It remains to be analyzed why the precursor lesions of these IDHmut secondary glioblastomas
escaped clinical detection despite their long clinical history.
Localization
Lai and colleagues (68) reported that glioblastomas lacking IDH1 mutations show widespread anatomic distribution, whereas IDH1mut glioblastomas have a striking
Table 1. Primary and secondary glioblastomas: comparison of clinical versus genetic diagnosis
Primary glioblastoma
Fraction in a population
Mean age, y
Male/female ratio
Mean clinical history, mo
Median overall survival, mo
Surgery þ radiotherapy
Surgery þ radio/chemotherapy
Clinical
criteriaa
Genetic
criteria (IDH1wt)
Clinical
criteriaa
Genetic
criteria (IDH1mut)
94.7%
59–62
1.33–1.5
6.3
91.2%
56–61
1.2–1.46
3.9
5.3%
33–45
0.65–2.3
16.8
8.8%
32–48
1.0–1.12
15.2
4.7b
9.9
15
7.8b
24
31
(7, 13)
(7, 12, 13, 67, 70)
(7, 12, 13, 70)
(7, 13)
(7, 12, 13)
(7, 13)
(12)
18%
89%
20%
90%
42%
63%
54%
50%
(13, 80)
(13, 80)
4–7%
17–35%
4–7%
36–45%
31–52%
23–25%
6%
2–8%
47%
70%
0%
19–27%
73–88%
60–88%
57–80%
0–8%
19–20%
4–12%
54%
0–13%
8%
63%
100%
76–81%
(10, 12, 13)
(7, 10, 12, 13, 67, 91)
(36, 37)
(7, 10, 12, 13, 91)
(7, 12, 13, 91)
(7, 12, 13)
(9, 13)
(10, 12, 67)
(8)
(7, 13)
Histologic features
Oligodendroglial comp.
Necrosis
Genetic alterations
IDH1 mutations
TP53 mutations
ATRX mutations
EGFR amplification
CDKN2A deletion
PTEN mutations
19q loss
1p/19q loss
10p loss
10q loss
Secondary glioblastoma
35–39%
30–45%
24–26%
4%
67%
0–6.5%
7–22%
0–8%
32%
73%
References
Tumors were considered to be primary if the diagnosis of glioblastoma was made at the first biopsy, without clinical or histological
evidence of a preexisting, less malignant precursor lesion, whereas the diagnosis of secondary glioblastoma required histological and/
or clinical (neuroimaging) evidence of a preceding low-grade or anaplastic astrocytoma.
b
Data from population-based study: all the patients who were treated in different ways were included.
a
768
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Definition of Primary and Secondary Glioblastomas
predominance of frontal lobe involvement, in particular in
the region surrounding the rostral extension of the lateral
ventricles. Stockhammer and colleagues (75) showed that
IDH1/2mut WHO grade II astrocytomas tend to develop in a
frontal location, and that seizures were the initial symptom
in approximately 70% of patients. According to Zlatescu
and colleagues (76) oligodendroglial tumors with 1p/19q
losses occur most frequently in the frontal lobe and have a
tendency for widespread growth across the midline. Similarly, Laigle-Donadey and colleagues (77) showed that
oligodendrogliomas with 1p/19q loss were located predominantly in the frontal lobe. These observations suggest
that oligodendrogliomas, astrocytomas, and secondary
glioblastomas derived thereof originate from precursor cells
located in or migrating to the frontal lobe.
Extent of Necrosis
Already in his 1940 publication, Scherer noted "the
absence of extensive necrosis and peritumoral brain swelling in
secondary and their almost constant presence in primary glioblastomas may play a certain role in the clinical behavior of the
two types" (1). He attributed this to the slower growth rate
of secondary glioblastomas. It is now understood that a
hypoxia-mediated activation of the coagulation system
causes intravascular thrombosis, further increases intratumoral hypoxia, and leads to abnormal endothelial cell
proliferation and tumor necrosis (78, 79). Microvascular
proliferation is induced by VEGF, which shows a markedly
higher expression in primary than in secondary glioblastomas (71).
Histopathologically, large areas of ischemic and/or pseudopalisading necrosis are more frequent in primary (89%)
than secondary glioblastomas (63%; P ¼ 0.0014; ref. 80)
and glioblastomas without IDH1 mutations (90% vs. 50%;
P < 0.0001; ref. 13; Table 1). This was confirmed in clinical
MRI studies showing that necrosis was less frequent in
IDH1mut glioblastomas, while exhibiting more frequent
nonenhancing tumor components, larger size at diagnosis,
lesser extent of edema, and increased prevalence of cystic
and diffuse components (68).
Histologic Features
According to the 2007 WHO classification, histologic
criteria for the diagnosis of glioblastoma include nuclear
atypia, cellular pleomorphism, mitotic activity, vascular
thrombosis, microvascular proliferation, and necrosis
(29). Glioblastomas may show significant intertumoral and
intratumoral heterogeneity, both histologically and genetically (80–82) and this may also apply to glioma-initiating
cells (82, 83). This heterogeneity reflects genomic instability
and, occasionally, focal new clones arising as a result of
additional genetic alterations can be seen histologically (84,
85). Areas with oligodendroglioma-like components are
significantly more frequent in secondary than primary
glioblastomas (42% vs. 18%; P ¼ 0.0138; ref. 80) and,
accordingly, more frequent in IDH1mut glioblastomas than
in IDH1wt glioblastomas (54% vs. 20%; P < 0.0001;
www.aacrjournals.org
ref. 13; Table 1). An increase in the fraction of tumor cells
with oligodendroglial morphology in IDH1mut glioblastomas was also reported in a large study of 618 cases (68). This
is not surprising as secondary glioblastomas assumedly
share IDH1mut precursor cells with oligodendrogliomas
(Fig. 1).
Clinical Outcome
In a population-based study, the median overall survival
of clinically diagnosed secondary glioblastoma was 7.8
months, significantly longer than the survival of patients
with primary glioblastoma (4.7 months; P ¼ 0.003; ref. 7).
Similarly, the analysis of patients with glioblastoma who
were treated with surgery and radiotherapy showed that the
mean overall survival time of patients with IDH1mut glioblastoma was 27.1 months, more than twice as long as that
of patients with IDH1wt glioblastoma (11.3 months; P <
0.0001; ref. 13). Yan and colleagues (12) reported that
IDH1mut glioblastomas treated with radio/chemotherapy
had an overall survival time of 31 months, again twice as
long as IDH1wt tumors. A different response to therapy is
also supported by the observation that dose enhancement
did not improve the outcome of glioblastomas with a
proneural signature (containing IDH1mut cases), in contrast
to glioblastomas with neural, classical, or mesenchymal
signature, which all profited from more intensive therapy
(61). If confirmed in prospective clinical trials, this may
eventually allow for dose deescalation in patients with
secondary glioblastoma.
Origin of Primary and Secondary Glioblastomas
Before the discovery of IDH1 mutations as a lineage
marker, it was assumed that primary and secondary glioblastomas developed from the same precursor cell population but showed distinct clinical and biologic behavior
due to the acquisition of different genetic alterations (6).
There is now increasing evidence that despite their similar
histologic features, primary and secondary glioblastomas
develop from different cells of origin. The evidence supporting this hypothesis includes the observations that: (i) only
secondary glioblastomas but not primary glioblastomas
share common IDH1/2 mutations with oligodendrogliomas;
(ii) primary and secondary glioblastomas develop in patients
of different age groups and have a different sex distribution;
(iii) primary and secondary glioblastomas are located in
different brain regions; and (iv) primary and secondary
glioblastomas have a significantly different clinical outcome.
All these data suggest that primary and secondary glioblastomas are in fact different tumor entities that are derived
from distinctly different neural precursor cells.
There is also evidence that cancer stem cells in primary
and secondary glioblastomas may also be different. In one
study, the relative content of CD133þ cells was significantly higher in primary than in secondary glioblastomas, and
CD133þ expression was associated with neurosphere formation only in primary but not secondary glioblastomas
(86).
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769
Published OnlineFirst December 3, 2012; DOI: 10.1158/1078-0432.CCR-12-3002
Ohgaki and Kleihues
Phenotype/Genotype Correlations
Despite differences in clinical history and genetic, epigenetic, and expression profiles, primary and secondary glioblastomas are histologically largely indistinguishable,
except that extensive necrosis is more frequent in primary
glioblastomas and oligodendroglioma components are
more frequent in secondary glioblastomas (80; Table 1).
This similarity may be attributable to genetic alterations that
are common to both primary and secondary glioblastomas.
The most frequent genetic alteration shared by both
primary and secondary glioblastomas is LOH at 10q
(60% of cases; refs. 6–8, 87–89), the most commonly
deleted region being 10q25-qter, distal to D10S1683 (8).
Because mutations of the PTEN gene located at 10q23.3
prevail in primary glioblastomas (25%), but are rare in
secondary glioblastomas (<5%; refs. 6, 7, 90), loss of
function of gene(s) other than PTEN is likely to be responsible for the common malignant phenotype. Circumscribed
glioblastoma foci in low-grade diffuse astrocytoma or anaplastic astrocytoma show additional deletions at 10q25qter, distal to D10S597, including the DMBT1 and FGFR2
loci (84). This suggests that the acquisition of a highly
malignant glioblastoma phenotype is associated with loss
of putative tumor suppressor gene(s) on 10q25-qter.
Pace of Malignant Progression to Secondary
Glioblastoma
The ability to predict the pace of progression from lowgrade diffuse astrocytoma to secondary glioblastoma would
be clinically very important by giving oncologists a rational
basis for deciding whether and at which stage to administer
adjuvant radiotherapy. Histopathologically, this is not possible, as Scherer noted already in 1940: "Why certain astrocytomas become transformed into glioblastomas while others
remain pure, is still obscure. No morphological sign explaining
or announcing this tendency could be found" (1).
When commonly deleted genes at 10q25-qter in IDHwt
and IDHmut glioblastomas were searched for in The Cancer
Genome Atlas (TCGA; ref. 91), 10 genes were identified
with log-ratio thresholds of 1.0, and, of these, DMBT1 at
10q26.13 was the only homozygously deleted gene in
glioblastomas with or without IDH1 mutations (12.5% vs.
8.0%; ref. 92). DMBT1 homozygous deletion was detected
at a similar frequency in an independent set of primary and
secondary glioblastomas (20% vs. 21%; ref. 92). A small
fraction (11.3%) of diffuse astrocytomas WHO grade II also
showed a DMBT1 homozygous deletion, and this was
significantly associated with shorter overall patient survival
(92). A similar approach was used to search for commonly
amplified genes in IDHwt and IDHmut glioblastomas in the
TCGA database. A total of 25 genes were identified, of which
21 were located at 7q31-34 (93). Further analyses revealed
gain of the MET gene at 7q31.2 in primary glioblastomas
(47%) and secondary glioblastomas (44%). Interestingly,
MET gain is also common in diffuse astrocytomas (38%),
and was associated with shorter survival (93). These results
indicate that several genetic alterations frequent in both
primary and secondary glioblastomas may be responsible
for the common histologic phenotype and, if already present in diffuse astrocytomas, may predict unfavorable clinical outcome (92, 93). Whole-genome DNA sequencing of
diffuse astrocytomas (WHO grade II) and anaplastic astrocytomas (WHO grade III) in patients with favorable or poor
outcome is likely to identify further genetic alterations that
drive the malignant progression to secondary glioblastoma.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: H. Ohgaki, P. Kleihues
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): H. Ohgaki
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H. Ohgaki, P. Kleihues
Writing, review, and/or revision of the manuscript: H. Ohgaki, P.
Kleihues
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): H. Ohgaki, P. Kleihues
Study supervision: H. Ohgaki
Received September 19, 2012; revised October 30, 2012; accepted November 5, 2012; published OnlineFirst December 3, 2012.
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Clinical Cancer Research
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Published OnlineFirst December 3, 2012; DOI: 10.1158/1078-0432.CCR-12-3002
The Definition of Primary and Secondary Glioblastoma
Hiroko Ohgaki and Paul Kleihues
Clin Cancer Res 2013;19:764-772. Published OnlineFirst December 3, 2012.
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